At a Glance

Isopropanol (2-propanol; IPA) intoxication should be considered in any patient in whom there is rapid unexplained loss of consciousness or central nervous system (CNS) depression, particularly with a history of a liquid ingestion and fruity aroma on the breath. The demonstration of ketonemia and ketonuria without an anion gap metabolic acidosis should lead to suspicion of IPA, rather than another toxic alcohol or glycol ingestion. Ketosis is present due to metabolism of IPA to acetone, and both contribute to the elevated osmolal gap.

IPA is present in a variety of household cleaning products, mouthwashes, rubbing alcohol, and antifreeze preparations. Inhalation and dermal absorption are significant routes of exposure, especially in infants or where there is dermal damage. Effort should be made to identify the source of the exposure. A toxic dose is less than 1g/kg.

IPA intoxication is predominantly a picture of CNS depression. Ethanol ingestion should be excluded, since this produces similar clinical features and increases the residence time of the IPA. Coingested hypnotics, such as benzodiazepines, barbiturates, opioids, and gamma hydroxybutyrate (GHB), markedly increase the risk of deep coma with respiratory failure after IPA ingestion.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Establishment of the presence of both IPA and its metabolite acetone in the serum or urine establishes the diagnosis of IPA exposure, and this documentation is invaluable if there are medico-legal or forensic sequelae.

However, there are no rapid laboratory or point of care tests for IPA, and its presence must be established by gas chromatography. This test also detects acetone and other small alcohols and provides quantitative results. The limited availability and delay in reporting of this test means that diagnosis and treatment decisions must be based on history and other tests.

If IPA and acetone analysis are not available, measure the serum osmolality by Freezing Point Depression (Vapor Dew Point Pressure methods are not reliable with volatile osmolytes). Osmolality will be elevated, and there will be a larger than normal osmolal gap. The demonstration of ketonemia and ketonuria without an anion gap metabolic acidosis should lead to suspicion of IPA, rather than another toxic alcohol or glycol ingestion. Ketosis can be detected by routine test strips due to metabolism of IPA to acetone, and both contribute to the elevated osmolal gap.

Urine osmolality will also be elevated in IPA intoxication, but this is not as useful in making the diagnosis as it is naturally more variable than serum.

It is important to determine whether ethanol is present by a qualitative test, and, if positive, a quantitative serum or breath ethanol should be obtained. Its presence will contribute to both the CNS depression and the osmolal gap and will reduce the speed with which IPA can be eliminated.

Alcoholic aroma with history and signs/symptoms of intoxication are not sufficient to establish the diagnosis beyond doubt, as this can be seen in diabetic ketoacidosis, which can be ruled out if blood or urine glucose is not grossly elevated, and in ethanol intoxication. Blood glucose is normal in IPA intoxication, even with ketosis, unless the patient has concomitant diabetes.

IPA concentrations do not correlate perfectly with clinical effects in adults or children, although the degree of CNS depression is several times greater than at the corresponding ethanol concentration.(Table 1)

Table 1

Test Results Indicative of the Disorder

Iso-Propanol

Acetone

Electrolytes and Blood Gas

Osmolality

Ketones

Serum

>10 mg/dL positive

50-100 mg/dL intoxication

Serum > 10 mg/dL at 30 mins after ingestion

Normal pH, bicarbonate, pCO2, lactate

Elevated > 300 mOsm/kg

Serum positive

>150 mg/dL coma

Continues rising, peaking as late as 4-12 hrs after ingestion

Anion gap <10 mmol/L

Osmolal Gap > 20 mOsm/kg, only slowly declining but not increasing

Urine positive

>450 mg/dL cardiovascular depression

Urine > 20 mg/dL after 3 hrs

Urine >20 mg/dL

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Isopropanol is stable in serum, but, if ethanol is measured at the same time, the sample should ideally be collected with fluoride oxalate preservative.

IPA and acetone do not interfere significantly with the current generation of rapid enzymatic laboratory or Point of Care ethanol determinations or with modern breath ethanol analyzers.

If IPA analysis is not available, measure the serum osmolality by Freezing Point Depression (Vapor Dew Point Pressure methods are not reliable with volatile osmolytes). Osmolality will be elevated, and there will be a larger than normal osmolal gap. For calculation of the osmolal gap, a simultaneous measurement of serum sodium, glucose, and blood urea nitrogen (BUN) is required. This information can be used to calculate the amount of IPA produced by the observed gap as follows, remembering to account for the gap attributable to any ethanol present:

If the diagnosis is based history and the presence of an osmolal gap, remember that the presence of other small osmolytes (i.e., ethanol, methanol, ethylene, or propylene glycol) will also contribute to the osmolal gap. A number of intravenous medications contain significant amounts of propylene glycol, and some accumulation of propylene glycol may be expected, which will contribute to the osmolality.

Acetone produced metabolically from IPA may falsely elevate serum and urine creatinine determined by Jaffe reaction.

What Lab Results Are Absolutely Confirmatory?

Isopropanol and acetone analysis by gas chromatography is the gold standard for both identification and quantitation and allows for simultaneous detection (and frequently quantitation) of ethanol, methanol, and acetone.

The ratio of the IPA to the acetone in serum changes with time. Generally, all the IPA has been eliminated from the serum in about 10 hours, and, after this time, the presence of acetone may be the only clue to the IPA ingestion.

Once diagnosis is established, it is not usually necessary to perform repeat measurements, unless intoxication does not resolve in the expected time frame.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

A variety of home-brew solvent screens may be offered, and it is important to ascertain exactly what compounds are included, otherwise a diagnosis might be missed. Specimens for these screens are often requested in specific containers with special handling conditions, but should always be drawn with minimal airspace to avoid loss during transport.

Standard of care tests are needed for treatment. Once diagnosis is established, it is not usually necessary to perform repeat measurements, unless intoxication does not resolve in the expected time frame. The patient can be reliably followed by osmolal gap measurements, since both unchanged IPA and metabolite acetone contribute equally to the osmolal gap.

If metabolic acidosis does occur, a search for other ingested substances is prudent, unless the metabolic acidosis can be attributed to inadequate tissue perfusion following cardiovascular collapse after massive IPA ingestion.

IPA is unusual among the alcohols in that hemorrhagic gastritis occasionally occurs. Monitoring of complete blood count (CBC) or stool occult blood, along with blood pressure, will alert to this event.

Urine pregnancy test should be performed in age-appropriate females.

A urine drug screen should be requested, if there is suspicion that other agents are involved. This can be a set of simple immunoassays for recreational drugs, which can be performed as a Point of Care or a laboratory-based test. Laboratory-based tests frequently include acetaminophen and salicylate, and more extensive investigations may be available in some institutions. This determines whether the clinical picture is due to ethanol alone or is confounded by coingestion of sedative-hypnotic agents, such as benzodiazepines, barbiturates, opioids, or GHB.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Ethylene and propylene glycol are nephrotoxins and cause elevations in serum creatinine and BUN, and ethylene glycol additionally produces calcium oxalate crystaluria and profound hypocalcemia. Hyperosmolar hyperglycemic coma presents with markedly elevated glucose concentration (often >900 mg/dL glucose without ketosis or fruity odor), which adds 50 mOsmol/kg to the measured osmolality, but the gap will not be elevated, since glucose is included in the osmolality calculation.

Critically ill patients may have elevated osmolal gaps. Ruling out IPA intoxication on the basis of a normal osmolal gap is unjustified.

A number of intravenous medications contain significant amounts of propylene glycol to solubilize the drug at physiological pH. This can result in a significant exposure, and, if the dose is greater than 25 mg/kg/day, some accumulation of propylene glycol may be expected. This contributes to the osmolality in a predictable fashion:

Serum PG mg/dL / 7.6 = mOsm/kg

Ketones

Urine test strips for ketones are highly sensitive to endogenously produced ketones and are strongly positive to the acetone produced from IPA metabolism. If the test is only weakly positive (and ethanol is not present to delay acetone production), then ingestion was not significant.

Creatinine

A number of serum and urine creatinine assays are falsely elevated by the presence of acetone. Picric acid forms a fast-reacting product with acetone, so assays that have measurement delays are less affected, as are those based on creatinase chemistry. This interference is not as great as commonly believed.

Isopropanol Metabolism

Some 80% of an IPA dose is metabolized in the liver by alcohol dehydrogenase (ADH), producing the ketone acetone, which cannot be further metabolized but must be eliminated by the kidney or lungs. The remaining 20% is eliminated unchanged in the urine. Ethanol and IPA are competitive substrates for ADH, and the Michaelia Constant (Km) for IPA is about 10 times that of ethanol. When the ingested dose of IPA is greater than several grams, the formation of acetone exceeds its elimination.

Expected Kinetics

Peak IPA concentrations occur at 0.5-2 hours after ingestion, whereas peak concentrations of acetone do not occur for at least 4-12 hours. Elimination half-life is 3-16 hours for IPA, and this increases substantially when ethanol is present (to almost 30 hours). Acetone appears in the blood at about 30 minutes postingestion, and its elimination is slow with a half-life of 8-24 hrs. Acetone appears in the urine at 3 hours postingestion (or longer if ethanol is present).